Polymeric tubes with controlled orientation

ABSTRACT

Methods for preparing oriented polymer tubes, such as biodegradable polymer tubes suitable for in vivo use, are provided herein. The disclosed methods provide alternatives to the typical extrusion/expansion methods by which oriented polymeric tubes for such uses are commonly produced. Advantageously, the disclosed methods can provide more homogeneous molecular orientation of crystallizable polymers within the tube walls, which can endow such polymeric tubes with enhanced strength (e.g., resistance to compression) and toughness.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication 62/555,796, filed Sep. 8, 2017, which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present application is directed to polymeric tubes with particularmolecular orientations, which find application in a variety of fields.

BACKGROUND OF THE INVENTION

Polymeric tubes are widely used for a number of applications. Polymericbioabsorbable tubes, in particular, can be designed for implantationwithin the body (e.g., within blood vessels and arteries) to serve asscaffolds to replace traditional metal stents. Some polymericbioabsorbable tubes find use as nerve guide tubes and/or as placeholderswithin the body for regeneration of nerve tissue. Other polymericbioabsorbable tubes can be designed as drainage tubes for the evacuationof fluids and/or gases from a body cavity or wound, e.g., to promotehealing. Advantageously, polymeric bioabsorbable tubes are prepared withbiodegradable polymer(s) and thus, can dissolve or be absorbed by thebody over time, eliminating the need for surgical removal of the tubesafter use.

Polymeric biodegradable tubes generally comprise one or morebiodegradable polymers, e.g., including, but not limited to,poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(D,L-lactide)(PDLLA), poly(E-caprolactone) (PCL), polyglycolic acid (PGA),poly(para-dioxanone) (PDO), poly(trimethylene carbonate) (PTMC),poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),poly(propylene glycol) (PPG), and copolymers, blends, and derivativesthereof. Selection of the polymer or polymers to produce a polymericbioabsorbable tube can have implications on both thebiocompatibility/toxicity properties of the resulting tube and thephysical/mechanical properties of the resulting tube, e.g., rate ofdegradation, strength (e.g., radial strength), and recoil rate.

One common means for producing such polymeric tubes (and, in particular,single-layer, thick-walled polymeric tubes) involves extrusion andannular expansion processes. Using such methods, a polymer is extrudedinto a tubular form, and the resulting tubular form isstretched/expanded annularly to provide a polymeric tube. Molecularorientation within the polymeric tube wall, as provided by the annularexpansion, is generally advantageous as it leads to increased strengthand/or heat shrinkable properties. However, known extrusion and annularexpansion processes are inherently limited as to the degree of molecularorientation possible throughout the wall thickness of the polymerictube. Further, due to the tubular structure, a gradient of molecularorientation may be present throughout the thickness of the wall, as withannular expansion, the inside diameter of a tube is generally subjectedto greater stretching/molecular orientation than the outside diameter ofthe tube. As such, it would be beneficial to provide methods forcontrolling the molecular orientation within polymeric tube walls and toprovide polymeric tubes with walls exhibiting such controlled molecularorientation.

SUMMARY OF THE INVENTION

The present invention relates generally to methods for the production ofpolymeric tubes and to polymeric tubes produced by such methods.Polymeric tubes for use, e.g., in biomedical applications, are generallyexpanded/stretched in some fashion to induce molecular orientationwithin the tube walls, which affords increased strength (e.g.,resistance to radial compression). The novel methods disclosed herein,involving producing polymeric tubes and molecularly orienting thepolymers therein to give oriented polymeric tubes, advantageously employplanar stretching and/or multi-layer annular expansion processes. Aswill be disclosed herein, by modifying the process by which moleculesare oriented within a polymeric tube (with respect to the typicalextrusion/annular expansion method for providing such oriented polymerictubes), tubes can be provided which exhibit modified crystallinitycharacteristics and, in some embodiments, corresponding enhancedstrength (e.g., enhanced resistance to radial compression) and/orcontrolled heat shrinkable properties.

In one aspect, the present disclosure provides a method for producing anoriented polymeric tube, comprising: subjecting a polymeric materialcomprising a crystallizable biodegradable polymer and having a firstdimension to planar stretching to increase the first dimension to give astretched polymeric material exhibiting at least partial molecularorientation; and forming the stretched polymeric material and anadhesive polymeric material into a tubular form, (which can also bereferred to as a tube or an oriented polymeric tube). As an example, theadhesive polymeric material adheres adjacent layers of the stretchedpolymeric material to itself or to other layers within the tubular form.The polymeric material can, in some embodiments, be a polymer film and,in some embodiments, can be a polymer profile.

In certain embodiments, the polymeric material has a second dimensionand the subjecting step further comprises stretching the polymericmaterial to increase the second dimension to give a biaxially orientedpolymeric material. The adhesive polymer material can be associated withthe crystallizable biodegradable polymer at varying stages of thedisclosed method. For example, in one embodiment, the above methodfurther comprises combining the adhesive polymeric material with thecrystallizable biodegradable polymer prior to the subjecting step togive a polymeric material that is a composite polymeric material withthe crystallizable biodegradable polymer and adhesive polymeric materialin layered form. In another embodiment, the above method furthercomprises combining the adhesive polymeric material with the stretchedpolymeric material prior to the forming step.

The forming step, in certain embodiments, comprises wrapping thepolymeric material and adhesive polymeric material around a cylindricalform. In some embodiments, such wrapping comprises wrapping thepolymeric material and adhesive polymeric material around thecylindrical form multiple times, giving a tube comprising multiplelayers of the stretched polymeric material and multiple layers of theadhesive polymeric material. The cylindrical form can vary and can be,e.g., a mandrel, wherein the method further comprises removing the tubefrom the mandrel. In some embodiments, the cylindrical form comprises adevice.

In another aspect, the disclosure provides a method for producing anoriented polymeric tube, comprising: obtaining at least two polymerictubes, each polymeric tube comprising a crystallizable biodegradablepolymer; annularly expanding the at least two polymeric tubes to produceat least two oriented polymeric tubes; and combining the at least twooriented polymeric tubes and one or more adhesive polymeric materialsinto a multi-layer tubular form. In some embodiments, the annularexpansion step is done before the combining step. In some embodiments,the combining step is done before the annular expansion step, and insome embodiments, the combining step is done during the annularexpansion step (i.e., the at least two oriented polymeric tubes and theadhesive polymeric materials are combined during the annular expansionof the at least two polymeric tubes).

This method can, in some embodiments, further comprise combining theadhesive polymeric material with one or more of the at least twopolymeric tubes prior to the annular expansion step to give one or morepolymeric tubes that are composite polymeric tubes, with thecrystallizable biodegradable polymer and the adhesive polymeric materialin layered form. The method can, in some embodiments, further comprisecombining the adhesive polymeric material with one or more of the atleast two polymeric tubes (prior to or after the annular expansion step)to give one or more polymeric tubes that are composite polymeric tubeswith the crystallizable biodegradable polymer and the adhesive polymericmaterial in layered form. In certain embodiments, the method referencedabove and described in more detail herein below further comprise a stepof fusing the tubular form by subjecting the multi-layer tubular form toheat, pressure, or both heat and pressure. Pressure can be eitherpositive or negative pressure, e.g., including pulling a vacuum to formthe tube (such as by applying vacuum through a perforated mandrel). Thefusing step may, for example, comprise applying a shrink tube or shrinkfilm around the tubular form to give a layered structure beforesubjecting the tubular form/layered structure to heat, pressure, or bothheat and pressure. The composition of the shrink tube or shrink film canvary and can comprise one or more materials selected, for example, fromthe group consisting of fluoropolymers (e.g.,poly(tetrafluoroethylene)), polyolefins (e.g., low-density polyethylene(LLDPE)), polyurethanes, and/or silicone polymers (e.g.,polydimethylsiloxane, PDMS) and combinations thereof.

In the context of any of the methods disclosed herein, thecrystallizable biodegradable polymer in certain embodiments is selectedfrom the group consisting of poly(L-lactide) (PLLA), poly(D-lactide)(PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid (PGA),poly(para-dioxanone) (PDO), poly(hydroxybutyrate),poly(hydroxyvalerate), poly(tetramethyl carbonate), poly(ethylene oxide)(PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), andcopolymers, blends, and derivatives thereof. The adhesive polymericmaterial is selected, for example, from the group consisting ofpoly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-Lactide)(PDLLA), poly(L-Lactide-co-ε-caprolactone),poly(L-Lactide-co-trimethylene carbonate),poly(ε-caprolactone-co-trimethylene carbonate), poly(ethylene glycol),poly(L-lactide-co-poly(ethylene glycol)), and copolymers and derivativesand combinations thereof. It is noted that these lists are not intendedto be exclusive, i.e., the same polymer or polymers may be present asboth a crystallizable biodegradable polymer and as an adhesive polymerwithin a given product, which may vary with respect to molecularorientation (e.g., where the polymer has greater molecular orientationas the crystallizable biodegradable polymer component and lessermolecular orientation as the adhesive polymer component). As such, thedisclosure encompasses, in certain embodiments, methods and productswherein the crystallizable biodegradable polymer and the adhesivepolymeric material comprise the same polymer with different orientations(e.g., different amounts of orientation).

The present disclosure further provides oriented polymeric tubesprepared according to any of the methods disclosed herein. Some suchoriented polymeric tubes primarily comprise the crystallizablebiodegradable polymer, with a minimal amount of adhesive polymericmaterial. In some embodiments, such oriented polymeric tubes arecharacterized by molecular orientation of the crystallizablebiodegradable polymer that is substantially consistent through a wall ofthe oriented polymer tube.

A further aspect provides a method for producing an oriented polymerictube, comprising: determining a desired geometry and molecularorientation profile for the oriented polymeric tube; selecting one ormore polymeric tube precursors comprising a biodegradable,crystallizable polymer; positioning the one or more polymeric tubeprecursors; and forming the one or more polymeric tube precursors intothe oriented polymeric tube exhibiting the desired final tubulargeometry and molecular orientation profile. The geometry and molecularorientation profile can be determined, e.g., based on one or more of:(i) a desired mechanical property of the oriented polymer tube to beformed; (ii) a desired thermodynamic property of the oriented polymertube to be formed; and (iii) a desired chemical property of the orientedpolymer tube to be formed.

In some embodiments, at least one of the one or more polymericprecursors are selected based at least in part on: (i) a composition ofthe one or more polymeric precursors, (ii) a geometry of the one or morepolymeric precursors, (iii) a mechanical property of the one or morepolymeric precursors, (iv) a thermodynamic property of the one or morepolymeric precursors, (v) a chemical property of the one or morepolymeric precursors, (vi) a degree of molecular orientation of the oneor more polymeric precursors, (vii) a molecular orientation profile withrespect to one or more axes of the one or more polymeric precursors,(viii) a predetermined method of forming the final polymeric tube fromthe one or more polymeric precursors, and any combination thereof. Insome embodiments, the one or more polymeric precursors are selected fromthe group consisting of: (i) one or more films, (ii) one or more tubes,and (iii) one or more profiles.

In particular embodiments, the one or more polymeric precursors are oneor more films or one or more tubes, and wherein the films or tubes arespecifically selected to contribute to the oriented polymeric tube oneor more of: (i) one or more specific mechanical properties, (ii) one ormore specific thermodynamic properties, (iii) one or more specificchemical properties, and (iv) one or more specific degradation rates. Inother particular embodiments, the one or more polymeric precursors areone or more profiles, and wherein the one or more profiles havecross-sectional shapes including but not limited to round, rectangular,triangular, elliptical, and tubular. In some embodiments, the one ormore polymeric precursors are one or more profiles, and wherein theprofiles are specifically selected to contribute to the orientedpolymeric tube one or more of: (i) one or more specific mechanicalproperties, (ii) one or more specific thermodynamic properties, (iii)one or more specific chemical properties, and (iv) one or more specificdegradation rates. Advantageously, in some of these embodiments, the oneor more polymeric precursors further comprise a tie layer.

The positioning of the one or more polymeric precursors, in someembodiments, comprises one or more of: (i) positioning the one or morepolymeric precursors around a mandrel (or other support, as describedherein below), and (ii) positioning the one or more polymeric precursorsinside a mold (which may be, in certain embodiments, expandable, e.g.,comprising a balloon). Positioning around a mandrel can comprise, forexample, positioning around a mandrel using a technique selected fromthe group consisting of wrapping, sheathing, winding, braiding, andcombinations thereof. The mandrel can, in some embodiments, comprise adevice. Positioning of the one or more polymeric precursors inside themold comprises: (i) positioning the one or more polymeric precursors ona mandrel and then inserting the one or more polymeric precursors on themandrel into the mold, and removing the mandrel, (ii) positioning theone or more polymeric precursors on a mandrel, and then removing themandrel and inserting the one or more polymeric precursors into themold, or (iii) positioning the one or more polymeric precursors insidethe mold during one or more production steps of the precursor.

The one or more production steps are selected, for example, from thegroup consisting of tube expansion, blow molding, injection-stretch blowmolding, die drawing, and mandrel drawing. The positioning comprises,for example, positioning of two or more polymeric precursors, whereinthe positioning of each polymeric precursor occurs simultaneously orsequentially. The forming can, in certain embodiments, further comprisefusing the one or more polymeric precursors by subjecting the one ormore polymeric precursors to heat, pressure, or both heat and pressure.Such fusing can comprise, for example, applying a shrink tube or shrinkfilm around the one or more polymeric precursors prior to subjecting theone or more polymeric precursors to heat, pressure, or both heat andpressure. Such fusing can comprise, for example, subjecting the one ormore polymeric precursors to heat, pressure, or both heat and pressureusing a mold and a balloon. In some such embodiments, the mold is linedwith the one or more polymeric precursors and a portion of the balloonwill make up a portion of the final polymeric tube. In such embodiments,the forming step can occur, e.g., during or after the positioning step.In some embodiments, two or more positioning steps and two or moreforming steps occur simultaneously or sequentially. Advantageously, insome embodiments, the one or more polymeric precursors comprise abiocompatible, biodegradable polymer, such as polymers including, butnot limited to, one or more polymers selected from the group consistingof poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone)(PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO),poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),poly(propylene glycol) (PPG) and copolymers, blends, and derivativesthereof.

The disclosure further provides an oriented polymeric tube preparedaccording to any of the methods outlined herein. Tubes according to thepresent disclosure can be characterized, e.g., by a molecularorientation profile that is substantially consistent through a wall ofthe oriented polymeric tube, a molecular orientation profile that issubstantially consistent through predefined portions of a wall of theoriented polymeric tube, a molecular orientation profile characterizedby varying levels of orientation through predefined portions of a wallof the oriented polymeric tube, a molecular orientation profilecharacterized by varying axes of orientation through predefined portionsof a wall of the oriented polymeric tube, a molecular orientationprofile characterized by an increasing molecular orientation gradientthrough a wall from the inner diameter to the outer diameter of theoriented polymeric tube, a molecular orientation profile characterizedby a decreasing molecular orientation gradient through a wall from theinner diameter to the outer diameter of the oriented polymeric tube, amolecular orientation profile that is substantially consistent through alength of the oriented polymeric tube, a molecular orientation profilethat is substantially consistent through predefined portions of a lengthof the oriented polymeric tube, a molecular orientation profilecharacterized by varying levels of orientation through predefinedportions of a length of the oriented polymeric tube, and/or a molecularorientation profile characterized by varying axes of orientation throughpredefined portions of a length of the oriented polymeric tube.

Tubes according to the present disclosure can be characterized, e.g., bya compositional profile that is substantially consistent through a wallof the oriented polymeric tube, by a compositional profile that issubstantially consistent through predefined portions of a wall of theoriented polymeric tube, a compositional profile characterized byvarying compositions through predefined portions of a wall of theoriented polymeric tube, a compositional profile that is substantiallyconsistent through a length of the oriented polymeric tube, acompositional profile that is substantially consistent throughpredefined portions of a length of the oriented polymeric tube, and/or acompositional profile characterized by varying compositions throughpredefined portions of a length of the oriented polymeric tube. Tubesaccording to the present disclosure can be characterized, e.g., by adegradation rate profile that is substantially consistent through a wallof the oriented polymeric tube, a degradation rate profile that issubstantially consistent through predefined portions of a wall of thepolymeric tube, a degradation rate profile characterized by varyingdegradation rates through predefined portions of a wall of the orientedpolymeric tube, a degradation rate profile characterized by anincreasing degradation rate gradient through a wall from the innerdiameter to the outer diameter of the polymeric tube, a degradation rateprofile characterized by a decreasing degradation rate gradient througha wall from the inner diameter to the outer diameter of the orientedpolymeric tube, a degradation rate profile that is substantiallyconsistent through a length of the oriented polymeric tube, adegradation rate profile that is substantially consistent throughpredefined portions of a length of the oriented polymeric tube, adegradation rate profile characterized by varying degradation ratesthrough predefined portions of a length of the oriented polymeric tube,and/or a degradation rate profile characterized by a degradation rategradient along the length of the oriented polymeric tube.

The disclosure further provides a method for producing an orientedpolymeric tube, comprising: determining a desired tubular geometry andat least one of a desired compositional profile and a desired molecularorientation profile; selecting one or more polymeric precursors;positioning the one or more polymeric precursors; and forming the one ormore polymeric precursors into the oriented polymeric tube exhibitingthe desired tubular geometry and at least one of the desiredcompositional profile and the desired molecular orientation profile.Certain specific embodiments are as follows:

Embodiment 1: A method for producing an oriented polymeric tube,comprising: obtaining at least one stretched polymeric materialexhibiting at least partial molecular orientation, wherein: theobtaining the at least one stretched polymeric material comprisingstretching at least one polymeric material, the at least one polymericmaterial comprising a first dimension, and at least one crystallizablebiodegradable polymeric material, and the at least one polymericmaterial being stretched in a manner that increases the first dimension;and forming the oriented polymeric tube using the at least one stretchedpolymeric material.

Embodiment 2: The method of the preceding embodiment, wherein thestretching comprises planar stretching.

Embodiment 3: The method of any preceding embodiment, wherein one ormore of the at least one polymeric material is one or more of a polymerfilm, a polymer monofilament, a polymer ribbon, a polymer tape, and apolymer rod.

Embodiment 4: The method of any preceding embodiment, wherein: the atleast one polymeric material has a second dimension, and the stretchingthe at least one polymeric material comprises stretching the at leastone polymeric material to increase the second dimension, wherein the atleast one stretched polymeric material comprises a biaxially stretchedpolymeric material.

Embodiment 5: The method of any preceding embodiment, wherein theforming comprises using the at least one stretched polymeric materialand at least one adhesive polymeric material.

Embodiment 6: The method of the preceding embodiment, furthercomprising: obtaining the at least one polymeric material based at leastin part on combining the at least one adhesive polymeric material withthe at least one crystallizable biodegradable polymeric material.

Embodiment 7: The method of the preceding embodiment, wherein the atleast one polymeric material is a composite polymeric materialcomprising the at least one crystallizable biodegradable polymericmaterial and the at least one adhesive polymeric material in layeredform.

Embodiment 8: The method of Embodiment 6, wherein the at least oneadhesive polymeric material and the at least one crystallizablebiodegradable polymeric material are combined before, during, or afterthe at least one polymeric material is stretched.

Embodiment 9: The method of Embodiment 6, wherein the forming the tubecomprises wrapping the at least one stretched polymeric material and theat least one adhesive polymeric material around a support.

Embodiment 10: The method of the preceding embodiment, wherein thesupport has one or more of a cylindrical shape, a round shape, arectangular shape, a triangular shape, an elliptical shape, a polygonalshape, and a tubular form.

Embodiment 11: The method of Embodiment 9 or 10, wherein the wrappingcomprises wrapping the at least one stretched polymeric material and theat least one adhesive polymeric material around the support multipletimes such that the tube comprises multiple layers of the at least onestretched polymeric material and multiple layers of the at least oneadhesive polymeric material.

Embodiment 12: The method of any of Embodiments 9-11, wherein: the atleast one stretched polymeric material comprises a plurality of units ofstretched polymeric material, the plurality of units of stretchedpolymeric material comprises different polymeric materials or a samepolymeric material; and the forming comprises arranging the plurality ofunits of stretched polymeric material in at least one of a stackedmanner and a staggered manner, and wrapping the arranged plurality ofunits of stretched polymeric material on a bias angle.

Embodiment 13: The method of any of Embodiments 9-12, wherein thesupport is a mandrel, and the method further comprises removing the tubefrom the mandrel.

Embodiment 14: The method of any of Embodiments 9-12, wherein thesupport comprises a device.

Embodiment 15: The method of Embodiment 14, further comprising forming aresulting composite based at least in part on the oriented polymerictube and the support, and the resulting composite is a medical device.

Embodiment 16: The method of any preceding embodiment, furthercomprising forming a medical device based at least in part on theoriented polymeric tube.

Embodiment 17: The method of the preceding embodiment, wherein theforming the medical device comprises: cutting the tube into a stent.

Embodiment 18: The method of the preceding embodiment, furthercomprising applying one or more of a therapeutic, a covering, and acoating to the stent.

Embodiment 19: The method of any preceding embodiment, wherein theforming comprises subjecting the at least one stretched polymericmaterial to at least one of heat and pressure.

Embodiment 20: The method of any preceding embodiment, wherein theforming comprises: forming a layered structure, the forming the layeredstructure comprising: applying a shrink tube or shrink film around atleast part of the at least one stretched polymeric material to give alayered structure, and subjecting the layered structure to at least oneof heat and pressure.

Embodiment 21: The method of any preceding embodiment, wherein theforming comprises: inserting at least part of the at least one stretchedpolymeric material in a mold; positioning the at least one stretchedpolymeric material over an expandable support; and subjecting the atleast one stretched polymeric material to at least one of heat andpressure.

Embodiment 22: The method of any preceding embodiment, wherein one ormore of the at least one crystallizable biodegradable polymeric materialis selected from the group consisting of poly(L-lactide) (PLLA),poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolic acid(PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate),poly(hydroxyvalerate), poly(tetramethyl carbonate), poly(ethylene oxide)(PEO), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), andcopolymers and derivatives and combinations thereof.

Embodiment 23: The method of any preceding embodiment, wherein theforming comprises using the at least one stretched polymeric materialand at least one adhesive polymeric material, and wherein the adhesivepolymeric material is selected from the group consisting ofpoly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide),poly(L-lactide)-co-ε-caprolactone), poly(L-lactide-co-trimethylenecarbonate), poly(ε-caprolactone-co-trimethylene carbonate),poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), andcopolymers and derivatives and combinations thereof.

Embodiment 24: The method of any of Embodiments 5-23, wherein theforming comprises using the at least one stretched polymeric materialand at least one adhesive polymeric material, and the at least onecrystallizable biodegradable polymeric material and the at least oneadhesive polymeric material comprise a same polymeric material.

Embodiment 25: The method of any preceding embodiment, wherein the atleast one stretched polymeric material is stretched at least ten percentof a maximum stretch ratio respectively corresponding to the at leastone polymeric material.

Embodiment 26: The method of any preceding embodiment, wherein thestretching the at least one polymeric material comprises controlling,during the stretching, one or more of a mechanical property, athermodynamic property, a chemical property, an electrical property, anda degradation rate, of the at least one polymeric material.

Embodiment 27: The method of any preceding embodiment, wherein the atleast one polymeric material is stretched between three hundred percentand one thousand percent of an original dimension of the at least onepolymeric material.

Embodiment 28: A method, comprising: obtaining at least one stretchedpolymeric material exhibiting at least partial molecular orientation,wherein: the at least one stretched polymeric material corresponds to atleast one polymeric material comprising a first dimension, and at leastone crystallizable biodegradable polymeric material, and the at leastone polymeric material having been stretched in a manner that increasedthe first dimension; and forming a tube using the at least one stretchedpolymeric material.

Embodiment 29: A tube, comprising: at least one stretched polymericmaterial exhibiting at least partial molecular orientation, the at leastone stretched polymeric material being obtained based at least in parton stretching at least one polymeric material, wherein the at least onepolymeric material comprises a first dimension, and at least onecrystallizable biodegradable polymeric material, the at least onepolymeric material, and wherein the at least one polymeric material isstretched in a manner that increases the first direction.

Embodiment 30: A tube, wherein: the tube comprises at least onecrystallizable biodegradable polymeric material, and an outer surfacethat has a normal that is perpendicular to a length of the tube, and thetube exhibits: a maximum stress value of about 20 MPa or greatermeasured based on a first compression cycle; and the tube being deformed17% or less in at least a first dimension after the first compressioncycle.

Embodiment 31: The tube of the preceding embodiment, wherein the firstcompression cycle comprises: obtaining an initial distance between twoparallel plates between which the tube is disposed, the two parallelplates contacting the outer surface of the tube in a manner in which thetwo parallel plates provide substantially no load on the tube;compressing the plates to a distance that is 50% of the initial distanceat a rate of 50% of the initial distance of the two parallel plates perminute, the compressing the plates causing the tube to deform in thefirst direction, the first direction being a direction in which theplates are compressed; and releasing a compression of the plates on thetube at a rate of 50% of the initial distance of the two parallel platesper minute.

Embodiment 32: The tube of Embodiment 30 or 31, wherein a total energyvalue under an engineering stress-strain curve corresponding to the tubeafter the first compression is at least 138 kgf·mm/cm.

Embodiment 33: The tube of any preceding embodiment, wherein the tubehas one or more of a therapeutic, a covering, and a coating appliedthereon.

Embodiment 34: A tube, wherein: the tube comprises at least onecrystallizable biodegradable polymeric material, and an outer surfacethat has a normal that is perpendicular to a length of the tube, thetube exhibits a maximum stress value of about 20 MPa or greater measuredbased on a first compression cycle; and a total energy value under anengineering stress-strain curve corresponding to the tube after thefirst compression is at least 138 kgf·mm/cm.

These and other features, aspects, and advantages of the disclosure willbe apparent from a reading of the following detailed descriptiontogether with the accompanying drawings, which are briefly describedbelow. The invention includes any combination of two, three, four, ormore of the above-noted embodiments as well as combinations of any two,three, four, or more features or elements set forth in this disclosure,regardless of whether such features or elements are expressly combinedin a specific embodiment description herein. This disclosure is intendedto be read holistically such that any separable features or elements ofthe disclosed invention, in any of its various aspects and embodiments,should be viewed as intended to be combinable unless the context clearlydictates otherwise. Other aspects and advantages of the presentinvention will become apparent from the following.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to provide an understanding of embodiments of the invention,reference is made to the appended drawings, which are not necessarilydrawn to scale, and in which reference numerals refer to components ofexemplary embodiments of the invention. The drawings are exemplary only,and should not be construed as limiting the invention.

FIG. 1 is a background (prior art) schematic representation of thetypical extrusion/expansion method for the production of single-layeroriented polymeric tubes;

FIG. 2 is a schematic representation of a method disclosed herein forthe production of oriented polymeric tubes via planar orientation andannular positioning;

FIGS. 3A-3C are schematic depictions of different techniques forwrapping polymer films to form polymeric tubes;

FIGS. 4A and 4B are schematic depictions of methods of aligning adjacentpolymer films to form polymeric tubes;

FIGS. 5A and 5B are schematic representations of certain methodsdisclosed herein for the production of oriented polymeric tubes viamultilayer annular orientation and annular positioning.

FIGS. 6A, 6B, 6C. show Max Stress, Normalized Energy and X-Interceptfrom cyclic compression tests for the Tubes from Example 3 and Example 4compared to a control tube.

FIGS. 7A, 7B, 7C. show Max Stress, Normalized Energy and X-Interceptfrom the cyclic compression tests for the Tubes from Examples 1, 3, 5and 7.

FIGS. 8A, 8B, 8C. show Max Stress, Normalized Energy and X-Interceptfrom the cyclic compression tests for the Tubes from Examples 2, 4, 6and 8.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described more fully hereinafter withreference to the accompanying figures, in which some, but not allembodiments of the inventions are shown. Indeed, these inventions may beembodied in many different forms and should not be construed as limitedto the embodiments set forth herein; rather, these embodiments areprovided so that this disclosure will satisfy applicable legalrequirements. Like numbers refer to like elements throughout.

The disclosure relates to methods to produce polymeric tubes (e.g.,biodegradable polymeric tubes) and to polymeric tubes produced thereby.In particular, the disclosure relates to methods to produce polymerictubes comprising a crystallizable polymer, involving a molecularorientation step to align/orient at least some of the molecules of thecrystallizable polymer within the walls of the tube (giving an orientedpolymeric tube). In various embodiments, the methods disclosed hereinprovide control over crystalline molecular orientation within thepolymeric tube walls, e.g., with respect to all three axes of acylindrical coordinate system. The methods disclosed herein, in certainembodiments, involve selecting a predetermined final tubular geometryand an associated predetermined molecular orientation profile andselecting materials and method steps accordingly, e.g., by positioningand forming one or more precursors so as to achieve the desired finaltubular geometry and molecular orientation profile. The disclosedmethods can advantageously provide oriented polymeric tubes exhibitingsufficient strength/resistance to radial compression to render themuseful in a range of applications, e.g., including, but not limited to,biomedical applications. The disclosed methods can also advantageouslyprovide oriented polymeric tubes exhibiting more controlled and improvedheat shrinkable properties with respect to tubes (e.g., oriented polymertubes) produced by traditional extrusion and annular expansion.

As referenced above, traditional methods for the production of orientedpolymeric tubes involve extrusion and annular expansion to providesingle-layer tubes. In such methods, a polymeric tube is extruded byconventional methods and then is subjected to annular expansion, asshown schematically in FIG. 1 (prior art). As shown in FIG. 1, theextruded tube 10 is produced with a given inner diameter (ID), which isrelated to the inner radius (shown as r_(i1)) via the equationOD=2×r_(i1), and a given outer diameter (OD), which is related to theouter radius (shown as r_(o1)) by the equation OD=2×r_(o1). The extrudedtube 10 is expanded (optionally under conditions of heat and pressure,as designated by T and P, respectively) to produce polymeric tube 12,with a larger ID (related to r_(i2) based on the equation above) and alarger OD (related to r_(o2) based on the equation above). With suchexpansion processes, the degree of stretching to which the ID of theextruded tube is subjected is greater than that to which the OD of theextruded tube is subjected. The differential in expansion rate andamount experienced by the ID and OD in such processes leads to animbalance in the degree of molecular orientation through the tube wall(i.e., from the ID to the OD). As described above, typical annularexpansion processes are limited as to the degree of orientationthroughout the final wall thickness, resulting in a decreasingorientation gradient from the ID to the OD.

According to the present disclosure, various methods are provided forproducing oriented polymeric tubes comprising a crystallizable polymer(e.g., a biodegradable crystallizable polymer, providing a resultingbiodegradable oriented polymeric tube). In some embodiments, such tubescan exhibit modified molecular orientation properties and correspondingmodified mechanical and/or thermodynamic properties with respect tooriented polymer tubes produced by traditional extrusion and annularexpansion. Modified molecular orientation properties in this regard canmean a greater percentage of molecular orientation in crystallineregions of the oriented polymeric tube and/or greater regularity in thedistribution of molecular orientation within crystalline regions of theoriented polymeric tube. For example, in some embodiments, the molecularorientation throughout the thickness of a wall of the disclosed orientedpolymeric tube is more uniform than that of a wall of an orientedpolymeric tube produced by conventional methods as shown in FIG. 1(leading to such improved mechanical and thermodynamic properties).Modified mechanical properties can mean higher strength, higher modulus,higher toughness, and/or greater elasticity. Modified thermodynamicproperties can mean modified heat shrinkable properties, including, butnot limited to, controlled shrinkage activation temperature, shrinkageforce, and shrinkage ratios.

Planar Orientation and Annular Positioning

One method provided herein involves use of uniaxially or biaxiallyoriented polymeric films as oriented precursors for the formation oforiented polymeric tubes (referred to herein as “planar orientation andannular positioning”). Orienting polymer molecules by stretching theminto uniaxially or biaxially oriented films is known to improveproperties such as tensile strength and toughness. See, e.g.,“Understanding biaxially and monoaxially oriented films”, PackagingWorld, Oct. 20, 2013.

One embodiment of the presently disclosed method is shown schematicallyin FIG. 2. According to this method, a polymer film comprising acrystallizable polymer, having a given dimension x₁ (considered here tobe the film length), is stretched in the planar direction to give astretched polymer film with corresponding dimension x₂, which is largerthan x₁ (i.e., the stretched polymer film is increased in length). Thestretched polymer film is referred to herein as an “oriented” polymerfilm, as the stretching process imparts at least some degree ofmolecular orientation within crystalline regions of the polymer film.

The polymer film can be of varying sizes and thicknesses, and the amountof stretching (related to x₁ and x₂ values) can, in some embodiments, bedetermined based on the desired thickness (z, not shown in FIG. 2) ofthe stretched/oriented film relative to the initial thickness of the(unstretched/unoriented) film. In some embodiments, the amount ofstretching (related to x₁ and x₂ values) can be determined based on thedesired mechanical and/or thermodynamic properties of thestretched/oriented film. The embodiment depicted in FIG. 2 provides foruniaxial stretching (stretching/increasing dimension x only); however,in some embodiments, the disclosed method involves biaxial stretching(stretching/increasing both dimensions x and y, i.e., length and width).In such embodiments, the stretching rates and/or amounts in both the xand y directions can be modified independent of each other. Planarstretching (in either one dimension only, i.e., uniaxially, or in twodimensions, i.e., biaxially) is advantageously done in a controlledmanner, such that the stretch rate, denoted by “k,” i.e., dx/dt (FIG. 2)is constant and the resulting stretched/oriented polymer film issubstantially homogeneous (e.g., in terms of thickness). Where theplanar stretching is uniaxial, as shown in FIG. 2, it is understood thatthe stretch rate for the other axis (here, along the y axis), dy/dt isequal to 0 (i.e., there is no stretching along the y axis). One of skillin the art would recognize that dy/dt is non-zero where there isstretching along the y axis.

The polymer film subjected to stretching can be produced by any of anumber of methods, including, but not limited to, extrusion, extrusioncoating, injection/blow molding, melt casting, solvent casting, orcompression molding (the latter two processes allowing for the use ofhigher molecular weight polymers than extrusion). In some embodiments,materials such as fillers can be dispersed into the polymer film priorto the stretching step. In certain embodiments, a tie layer material isassociated with the polymer film prior to stretching (such that both thepolymer film and the tie layer material are stretched together), as willbe described in further detail below. It is noted that, although theapplication is described specifically in the context of polymer filmsthat are stretched (and, as referenced below, polymer profiles), thedisclosure is not intended to be limited thereto. For example, in otherembodiments, a polymeric material in the form of a polymer monofilament,a polymer ribbon, a polymer tape, or a polymer rod is used. One of skillin the art is familiar with these terms and will appreciate, e.g., thata polymer monofilament is a threadlike synthetic fiber (which fibers canhave varying diameters), a polymer tape is a flattened strip ofpolymeric material (which tapes may have varying lengths and widths),and a polymer rod is a three-dimensional structure (although not limitedto being circular in diameter).As an example, a polymer rod can be acylindrical structure. As another example, a polymer rod can be atubular structure.

There are a number of methods known in the art to stretch a polymericmaterial in one or two dimensions as described above. In machinedirection (MD) stretching, an extruded film is cast onto a chill rollthen reheated and passed through a nip and over tensioning rollers atspeeds exceeding the extrusion casting speed to stretch the material. Asubsequent transverse direction (TD) stretching can be accomplished bygripping the sides of the film in clamps and pulling the clamps normalto the machine direction through a heated oven in a tenter frame.Alternatively, the MD and TD stretching can be accomplishedsimultaneously in a tenter frame capable of simultaneous biaxialorientation, such as a LISIM line manufactured by Brückner. The linespeeds, temperatures and stretching rates are controlled to achieve thedesired extent of stretching without tearing the film. Simultaneousstretching of the polymeric material can also be achieved by using ablown film line which extrudes the polymeric material through an annulardie and then inflates the extrudate with air to create a bubble whichserves to stretch the material in both TD and MD directions. Ifadditional MD or TD stretch is required, the blown film line can bemodified to provide a second bubble to achieve higher extents ofstretching in either or both MD and TD. There are many manufacturers ofindustrial blown film and double-bubble lines, such as Hosokawa Alpine,GAP srl. or Kuhne Group. In addition to the continuous processes hereinoutlined, batch-wise stretching can be achieved, in some embodiments, byclamping a polymeric film on all sides and stretching it in an oven inone or both of MD and TD sequentially or simultaneously. The Karo IVstretcher manufactured by Brückner provides one example of a batch-wisefilm stretcher.

The degree to which the polymer film is stretched can vary, asreferenced above. In some embodiments, the polymer film is stretched atleast ten percent of a maximum stretch ratio respectively correspondingto the at least one polymeric material. “Maximum stretch ratio” as usedherein is intended to mean the maximum stretch possible before tearingof the material occurs.

Using the stretched, oriented polymer film as a precursor for theformation of a tubular form, the stretched, oriented polymer film ispositioned in an annular configuration (e.g., by rolling or wrapping thestretched, oriented polymer film) and optionally further processed toprovide the oriented polymeric tube (e.g., the oriented biodegradablepolymeric tube). Although the present disclosure focuses on positioningthe stretched, oriented polymer film in an annular configuration byrolling/wrapping the film to provide a tubular form, other means forpositioning are also encompassed herein.

The stretched, oriented polymer film may optionally be further processedprior to this step, e.g., by cutting the film into individual desiredsizes and/or by associating a tie layer therewith, as will be describedin further detail below. Although not intended to be limiting, one meansfor positioning the stretched, oriented polymer film in an annularconfiguration comprises wrapping/rolling the film around a formingmandrel. It is noted that the shape of the forming mandrel is notparticularly limited. As such, a polymeric “tube” as used herein isunderstood to not be limited to cylindrical tubes. Rather, a polymeric“tube” produced according to the disclosed methods is any hollow,elongated structure, wherein the cross-sectional shape of the hollow,elongated structure may be, but is not limited to, being round.

The disclosed method further is not limited to wrapping/rolling the filmaround a mandrel; rather, the film can be wrapped around various typesof supports. Suitable supports include, but are not limited to, supportswith one or more of a cylindrical shape, a round shape, a rectangularshape, a triangular shape, an elliptical shape, a polygonal shape, and atubular form. In some embodiments, the support is a device or devicecomponent (e.g., including, but not limited to, a stent). In certainsuch embodiments, the method disclosed herein provides a compositecomprising the support and the positioned oriented polymer film, whichcan be in the form of a medical device. Particularly where the supportis a device and where the disclosed method provides a medical device,the composite can, in some embodiments, be further processed. Forexample, in some embodiments, one or more of a therapeutic, a covering,and a coating is applied to the composite. In some embodiments, thecomposite is cut into appropriate sizes for stents. Various methods areknown for cutting stents, including, but not limited to, laser cutting.

The oriented polymer film can, in some embodiments, be positioned byrolling/wrapping as described above to provide a single-layer orientedpolymeric tube with little to no overlap of one edge of the polymer filmwith the opposite edge of the film (e.g., with only a small seam wherethe two film ends meet) or by rolling/wrapping the film multiple timesto produce a multi-layer tube. More preferably, a multi-layer tube(e.g., a tube with a “layered structure”) is formed, having any numberof layers, wherein the number of layers is not particularly limited.Exemplary such multi-layer tubes have 2 to 20 layers of the orientedpolymer film, which preferably comprises a single oriented polymer filmwrapped/rolled so as to give the desired number of layers (e.g., toachieve the desired wall thickness of the resulting multi-layer orientedpolymeric tube). It is understood that, in such embodiments, a greaternumber of layers/wrappings will provide a polymeric tube with thickerwalls (assuming an oriented polymer film with the same thickness isused). As such, the number of layers/wrappings can dictate the wallthickness of the resulting oriented polymeric tube. The axis along whichthe polymer film is rolled/wrapped with respect to the axis/axes alongwhich the polymer film has been stretched/oriented can vary, as shown inFIGS. 3A-3C. The circular arrow indicates the direction of wrapping.

Typically, to provide sufficient adhesion between layers of adjacentoriented polymer films of such multi-layer polymeric tubes (e.g.,produced by positioning and forming multiple wrappings of one or morefilms), a tie layer (e.g., an “adhesive polymeric material”) asdescribed herein below is included within the oriented polymeric tube.In some embodiments, a tie layer is incorporated by associating a tielayer material with an (unstretched/unoriented) polymer film asdescribed herein above to provide a composite polymer film, andsubjecting this composite polymer film to planar expansion as describedabove. This associating can be done, e.g., by aligning a tie layermaterial film with the (unstretched/unoriented) polymer film or bycoating the (unstretched/unoriented) polymer film with the tie layermaterial, such as by extrusion coating or solution-coating the tie layermaterial onto the polymer film. This method provides both thecrystallizable polymer film and the tie layer in stretched form (and, insome such embodiments, this method could provide molecular orientationwithin not only the polymer film, but also within the tie layer).

In another embodiment, a tie layer is incorporated by associating a tielayer material with a stretched/oriented polymer film. In suchembodiments, a composite film is provided by subjecting a crystallizablepolymer film to stretching/orientation and subsequently associating atie layer material with the stretched, oriented polymeric film. Thisassociating can be done, e.g., by aligning a tie layer material filmwith the (stretched/oriented) polymer film or by coating the(stretched/oriented) polymer film with the tie layer material, such asby extrusion coating or solution-coating the tie layer material onto thepolymer film. The composite polymer film provided according to thisembodiment comprises the crystallizable polymer film instretched/oriented form, while the tie layer is inunstretched/unoriented form. Other modifications to these embodimentsare also encompassed, e.g., wherein a polymer film and tie layer areindependently stretched to give a stretched/oriented polymer film and astretched or stretched/oriented tie layer, which can be combined to givea composite polymer film.

As briefly noted herein above, the composition of the oriented polymerfilm(s) and the composition of the tie layer(s) can be the same ordifferent. As such, in certain embodiments, the composition of one ormore of the oriented polymeric films is the same as the composition ofone or more tie layers, but the polymers are oriented to differentextents (e.g., the oriented polymeric film(s) are oriented to a greaterdegree than the tie layer(s)).

The composite polymer film is then formed into an oriented polymerictube as provided herein above, such that the tie layer material isassociated with each “layer” (or wrap) of the oriented polymer film andbonds adjacent layers of the polymeric film together. The bonding may,in some embodiments, require treatment of the polymeric tube bysubjecting the final polymeric tube to heat and/or pressure. In someembodiments, the pressure is negative pressure, i.e., application ofvacuum to the tube, such as by pulling a vacuum through a mandrel aroundwhich the polymeric tube is wrapped. In some embodiments, heat and(positive) pressure are provided by wrapping the polymeric tube in ashrink material (e.g., a shrink tube or shrink wrap comprising linearlow-density polyethylene, LLDPE) and heating the wrapped polymeric tube(e.g., by placing the tube in an oven). The oven temperature, formingtime, and the forming pressure applied can depend on the components ofthe polymeric tube and these processing variables can each be controlledto tune the final oriented polymeric tube properties. In someembodiments, other bonding techniques can be employed, to replace orsupplement the heat/pressure method. For example, in some embodiments,bonding can employ contact with one or more solvents (e.g., chloroform)and in some embodiments, bonding can involve the use of radiofrequencywelding.

Although the planar orientation/annular positioning methods outlinedherein above are disclosed as comprising three distinct steps (planarorientation, e.g., stretching a polymer film, annular positioning, e.g.,positioning the oriented polymer film in an annular position, andforming, e.g., forming the positioned oriented polymer film into anoriented polymeric tube), the disclosed method can be modified so as toconduct two or all three of these steps largely simultaneously. Forexample, in some embodiments, a polymer film may be provided inunstretched form and can be stretched (and oriented) by air and/orliquid pressure against a cylindrical forming surface to form anoriented polymeric tube.

In some embodiments, rather than utilizing a stretched polymer film asthe polymeric tube precursor, an oriented composite polymer profile ispositioned and formed into a tube and thus can serve as the polymerictube precursor. This method involves positioning the oriented compositepolymer profile with respect to all three cylindrical axes according toa desired orientation profile. The positioning of the composite profilecan include, but is not limited to, wrapping, sheathing, winding, orbraiding. This positioned composite profile is subjected to pressureand/or temperature such that the tie layer(s) adhere to adjacent layersof the composite profile, thereby forming a coherent, multi-layeroriented polymeric tube.

A polymer profile is a shaped polymeric form (rather than a polymer filmas referenced above), which comprises a crystallizable polymer asdisclosed herein. Exemplary polymer profiles include, but are notlimited to, cross-sectional profiles in the form of squares, rectangles,polygons, ellipses, or other geometric shapes that may or may notpossess regular or intermittent features on one or more surfaces of theshape. A composite profile is a polymer profile (comprising acrystallizable polymer as referenced above), further comprising a tielayer material.

In certain embodiments, tubes produced by positioning and formingoriented films or profiles as outlined in this section exhibit a moreconsistent degree of molecular orientation across the tube wallthickness than that across the tube wall thickness of an extruded andradially expanded single-layer tube (produced as referenced above and asshown schematically in FIG. 1). Using a cylindrical coordinate systemand assuming two surfaces in full contact (excluding tie layers ofnegligible thickness) are geometrically continuous, such a tube formedfrom a round-shaped profile positioned to give maximum density will begeometrically discontinuous along all three axes. With respect tomolecular orientation and imposing geometrical continuity, such a tubewould be continuous along the θ-axis and discontinuous along the r-axisand z-axis. Such a tube formed from a rectangular-shaped profilepositioned to give maximum density will be geometrically discontinuousalong all three axes. With respect to molecular orientation and imposinggeometrical continuity, such a tube would be continuous along all threeaxes.

The planar orientation/annular positioning method disclosed hereinprovides a number of advantages as compared to traditionalextrusion/annular expansion. For example, according to the disclosedmethod, each polymer film (or profile) can be stretched uniaxially orbiaxially as desired, to the degree desired. Multiple polymers can, insome embodiments, be combined as individual layers in a compositestructure and stretched (and oriented) together. In some embodiments,multiple polymers can be independently provided in film or profile formand stretched (and oriented) to different extents and then theseoriented films and/or profiles can be combined before or during theforming of the polymeric tube.

The manner in which different polymer films (or profiles) can becombined may be varied to achieve different composite structures anddifferent properties. For example, in some embodiments, multiple filmscan be plied up on a bias angle during the tube forming process (e.g.,at the forming mandrel) to match critical application requirements.Various configurations of the component layers can be obtained duringproduction. For example, individual layers may be staggered or stackedwith respect to one another. In this context, stacked configurations(e.g., as shown in FIG. 4A) comprise different films directly on top ofeach other and staggered configurations (e.g., as shown in FIG. 4B)comprise different films offset such that when they are rolled (orotherwise formed into tubular form), the initial layer(s) is a singlematerial followed by one or more layer(s) of a composite film (orprofile), followed by one or more layers of the final material. A givenoriented polymer tube could further be provided with a stacked set oflayers and a staggered set of layers.

In some embodiments, individual films/layers can be selected for veryspecific properties such as strength, toughness, inclusion/elution ofdrugs, adhesion, surface functionality, degradability, etc., to affordsuch properties to the resulting polymeric tube. Additional componentscan be incorporated within the final tube at various stages of theproduction method outlined herein (e.g., between films that aresubsequently encapsulated by the tie layer(s) prior to or during theforming step), including, but not limited to, braids, fibers, wovens,nonwovens, and/or inserts. In some embodiments, oriented polymeric tubesprovided via the method disclosed herein can be further altered insubsequent steps to produce a medical device (e.g., by laser cutting,crimping, expansion, etc.).

Multilayer Annular Orientation and Annular Positioning

Another aspect of the present disclosure relates to methods involvingmultilayer annular orientation and annular positioning and to orientedpolymeric tubes produced thereby. As described above, one disadvantageof an annular expansion process is that the degree of orientationthroughout the final tube wall thickness is limited, resulting in adecreasing orientation gradient from the ID to the OD. This concern canbe addressed by employing an annular orientation approach, butminimizing the wall thicknesses, as the limitation on degree oforientation achievable approaches zero as the wall thickness approacheszero. Therefore multi-layer tubes formed from annularly oriented tubeprecursors where the wall thicknesses of the precursors become additivein the formation of the wall thickness of the final formed orientedpolymeric tube, will exhibit a higher degree of orientation throughoutthe tube wall thickness and a reduced orientation gradient from the IDto the OD of the final formed polymeric tube.

In this multilayer annular orientation and annular positioning approach,multiple polymeric tubes (which can be of the same composition ordifferent compositions) are prepared and subjected to annular expansion,thereby producing oriented tube precursors with at least some degree ofmolecular orientation, as shown in FIG. 5A (step 14 or 18). Suchpolymeric tubes can be made by any method, e.g., via extrusion,extrusion coating, and/or injection molding. In one embodiment, theindividual oriented tube precursors are positioned in a nested manner asshown in step 16. In another embodiment, oriented tube precursors arepositioned in a nested manner as shown in step 20, and then subjected toadditional annular expansion (simultaneously) as shown in step 22. Thepositioning of the oriented tube precursors in such embodiments iscompleted via the annular expansion step. The formation of the finaltubular geometry (giving an oriented multilayer polymeric tube) can becompleted via the annular expansion step or subsequent to the annularexpansion step.

In another embodiment, the annular expansion of the polymeric tubes cantake place sequentially, one within another, as shown in FIG. 5B.Following the annular expansion of the first tube (making up the outeroriented tube precursor), the annular expansion of each subsequent tubepositions an additional oriented tube precursor within the ID of thepreceding oriented tube precursor, resulting in the annular positioningof all oriented tube precursors. The formation of the final tubulargeometry (giving an oriented multilayer polymeric tube) can be completedvia the annular expansion of one or more tube precursors or subsequentto the annular expansion of one or more tube precursors. The annularexpansion for any of these embodiments can be conducted by any knownmethod for expanding tubes annularly.

Combining multiple unstretched/unoriented polymeric tube precursors orstretched/oriented tube precursors using this method can be conducted invarious ways, e.g., by forming the oriented polymeric tube on a mandrel(optionally with the application of heat and/or pressure) or by formingthe oriented polymeric tube within a mold (again, optionally with theapplication of heat and/or pressure). It is noted that such formingmandrels and molds are not required to be round in cross section, and assuch, the resulting multi-layer oriented polymeric tube can be in theform of a hollow, elongated structure that can be, but is not limitedto, being round in cross-section.

With the multilayer annular orientation and annular positioning method,due to the inclusion of multiple individual layers, a tie layer is againtypically incorporated between adjacent layers to provide sufficientadhesion there between. In these embodiments, the inclusion of a tielayer can be achieved, for example, by associating a tie layer materialwith one or more polymeric tube precursors (to provide compositepolymeric tube precursors), such that when the polymeric tube precursoris expanded/oriented and combined with other precursors (or combinedwith other precursors and then expanded/oriented), the tie layer issimilarly subjected to such processes as well. As such, in someembodiments, the tie layer is similarly subjected to annularexpansion/orientation. In other embodiments, the tie layer is appliedafter the individual polymer tubes have been expanded/oriented and insuch embodiments, the tie layer is not subjected to annularexpansion/orientation. Again, forming the final oriented polymer tube bybonding adjacent layers (arising from the combining of multiple tubeprecursors or multiple individually expanded/oriented tubes) may requiretreatment of the final oriented polymeric tube by subjecting themulti-layer oriented polymeric tube to heat and/or pressure. In someembodiments, heat and pressure are provided by wrapping the orientedpolymeric tube in a shrink tube or shrink wrap and heating, e.g., byplacing the wrapped oriented polymeric tube in an oven. The oventemperature and the forming pressure applied can each be controlled totune the final tube properties.

As such, in certain embodiments (e.g., as depicted by steps 16 and 22 inFIG. 5A), at least two oriented tubes (which each can comprise onecrystallizable polymeric layer and, optionally, one tie layer (giving acomposite oriented tube)) are positioned with respect to all threecylindrical axes according to a desired orientation profile. Thepositioned tubes are subjected to increased pressure and/or temperaturesuch that the tie layer adheres to adjacent layers (i.e., the orientedpolymer layers on either side thereof), thereby forming a coherentmultilayer oriented polymeric tube. In some embodiments, a compositestretched, oriented tube is positioned with respect to an outer and/orinner expanded/oriented tube comprising a crystallizable polymer (whichmay or may not comprise a tie layer).

In some embodiments (e.g., as depicted in FIG. 5B), non-orientedcomposite tubes (comprising both the crystallizable polymer and a tielayer material) are expanded annularly (e.g., under conditions ofelevated temperature and pressure), orienting at least a portion of thecrystallizable polymer. Via this annular expansion process, the tielayer material can, in some embodiments, adhere to any adjacent layers.For example, in this embodiment, one adjacent layer is thecrystallizable polymer of the same non-oriented composite tube precursorand the other adjacent layer can be an already oriented tube of a secondcrystallizable polymer (which may be the same as or different than thecrystallizable polymer in the composite tube precursor), thereby forminga coherent multi-layer oriented polymeric tube. In such embodiments, theindividual layers are positioned with respect to all three cylindricalaxes according to a desired orientation profile. The composite tubeprecursor can also be positioned with respect to an inner tube precursorcomprising the crystallizable polymer.

There are a number of methods known in the art to annularly expandpolymeric tubes as described above. In conventional blow molding, anextruded polymeric tube is disposed within a mold, heated to a rubberystate, and pressurized to expand the tube into the mold. In somemethods, the extruded polymeric tube is also stretched in the machinedirection by applying tension. The machine direction stretching iscompleted prior to or during the annular expansion. The final expandedtube geometry is generally determined by the geometry of the mold andthe process parameters such as temperature and pressure. The propertiesof the final expanded tube are generally determined by processparameters such as annular expansion ratio, annular expansion rate,machine direction stretch ratio, machine direction stretch rate,temperature, and pressure.

The multilayer annular orientation and annular positioning methoddisclosed herein provides a number of advantages as compared totraditional extrusion/annular extrusion. For example, each tubeprecursor can be oriented uniaxially or biaxially as desired, to thedegree desired prior to or during the formation of the multi-layeroriented polymeric tube, to match application requirements. Multiplepolymers can, in some embodiments, be combined as individual layers in acomposite structure and expanded/oriented together. In some embodiments,multiple polymers can be independently provided in tube form andexpanded (and thus oriented), e.g., to different extents and then theresulting oriented tubes can be combined during positioning and formingof the multi-layer oriented polymeric tube. In some embodiments,individual tubes and tube precursors can be selected for very specificproperties such as strength, toughness, inclusion/elution of drugs,adhesion, surface functionality, degradability, etc., to afford suchproperties to the resulting multi-layer polymeric tube. Additionalcomponents, e.g., fillers can be dispersed in one or more of the tubeprecursors prior to expansion. Additional components can be incorporatedwithin the final multi-layer polymeric tube at various stages of theproduction method outlined herein (e.g., between tubing layers that aresubsequently encapsulated by the tie layer(s) materials), including, butnot limited to, braids, fibers, wovens, nonwovens, and/or inserts. Insome embodiments, the multilayer polymeric tube provided via the methoddisclosed herein can be further altered in subsequent steps to produce amedical device (i.e., by laser cutting, crimping, expansion, etc.).

Using the cylindrical coordinate system and assuming two surfaces infull contact are geometrically continuous, such tubes (formed fromprecursor annular geometries) will be geometrically continuous along allthree axes. With respect to molecular orientation and imposinggeometrical continuity, such a tube would be continuous along the z-axisand the θ-axis and discontinuous along the r-axis.

The oriented polymeric tube production methods disclosed herein areapplicable to a range of crystallizable polymers. Such methods areparticularly applicable to biodegradable polymers (although not limitedthereto). As such, in preferred embodiments, the polymer(s) from whichoriented polymeric tubes are prepared according to the presentdisclosure are advantageously crystallizable biodegradable polymers andadvantageously are capable of exhibiting high molecular orientation,strain-induced crystallization, and high strength.

Biodegradable (also commonly referred to as “bioabsorbable” and/or“bioresorbable”) polymers are those polymers that will, under certainbiological conditions, undergo breakdown or decomposition into compoundsconsidered to be harmless/safe as part of a normal biological process.Advantageously, under the biological conditions to which they aresubjected, biodegradable polymers gradually degrade and/or erode and areabsorbed or resorbed within the body. Typically, biodegradable polymersapplicable in the context of the present disclosure are sufficientlystable under biological conditions to remain in the body for a durationof time (e.g., including, but not limited to, up to about 1 week, up toabout 1 month, up to about 3 months, up to about 6 months, up to about12 months, up to about 18 months, up to about 2 years, or longer) beforesubstantial degradation. Typically, such biodegradable polymers are alsobiocompatible.

Exemplary crystallizable polymers applicable in the context of thepresent invention include, but are not limited to, poly(L-lactide)(PLLA), poly(D-lactide) (PDLA), poly(ε-caprolactone) (PCL), polyglycolicacid (PGA), poly(para-dioxanone) (PDO), poly(hydroxybutyrate),poly(hydroxyvalerate), poly(tetramethyl carbonate), poly(ethylene oxide)(PEO), poly(ethylene glycol) (PEG), poly(propylene glycol),polydioxanone, polygluconate, and copolymers, blends, and derivativesthereof. Certain polymers that can be used according to the disclosedmethods can be characterized as poly(alpha-hydroxy acids). Some polymersare modified cellulosic polymers, collagen or other connective proteins,adhesive proteins, hyaluronic acid, polyanhydrides, polyphosphoesters,poly(amino acids), and copolymers and derivatives thereof. The molecularweight of the polymers processed according to the methods outlinedherein can vary and may affect the properties of the resulting orientedpolymeric tubes. It is generally understood that mechanical propertiesof polymers (e.g., strength and modulus) generally improve withincreasing molecular weight and that degradation time generallyincreases with increasing molecular weight (i.e., a tube made of a lowmolecular weight polymer typically degrades more quickly than acomparable tube made of a higher molecular weight polymer). As such,polymer molecular weights can be selected accordingly to balance theseproperties, and may vary widely, depending on the particularapplication.

As described above, the oriented polymeric tubes disclosed hereincommonly comprise, in addition to the oriented crystallizable polymer,one or more tie layer materials (also referred to herein as “adhesive”layer materials) sufficient to bind multiple layers together. Suchmultiple layers can comprise multiple layers of the same material (e.g.,in the case of a multi-layer material produced by wrapping) and/or cancomprise layers of different materials. Advantageously, in someembodiments, the tie layer bonds adjacent layers together such that theoriented polymeric tube exhibits little to no delamination during use(e.g., the adhesion between layers allows for the oriented polymerictube to undergo at least partial degradation without exhibitingsufficient delamination).

The composition of the tie layer(s) within the final oriented polymerictube can vary. Tie layers typically comprise one or more polymerscapable of bonding two adjacent layers together and as such, variouspolymers with adhesive properties may be used. Typical adhesive polymersfor use as tie layers exhibit some degree of flow and/or tackiness. Thepolymer(s) comprising the tie layers, in some embodiments (e.g., wherethe final product is designed for implantation within the body) arepreferably biocompatible, biodegradable polymers. The polymer(s)comprising the tie layers, in some embodiments, arenon-crystalline/substantially amorphous polymer(s). Exemplary polymersthat are suitable to serve as (or be included within) tie layersaccording to the present disclosure include, but are not limited to,poly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-Lactide),poly(L-Lactide)-co-ε-caprolactone), poly(L-Lactide-co-trimethylenecarbonate, poly(ε-caprolactone-co-trimethylene carbonate), poly(ethyleneglycol), poly(L-lactide-co-poly(ethylene glycol)), and copolymers andderivatives and combinations thereof.

The properties of tubes produced by the foregoing methods can vary. Forexample, the geometric continuity and orientation continuity of orientedpolymeric tubes prepared by the various methods are compared below inTable 1.

TABLE 1 Geometric/orientation continuities for tubes prepared accordingto disclosed methods Geometric Continuity Orientation Continuity z-axisr-axis Θ-axis z-axis r-axis Θ-axis Rolled x — — x x x Film(s) Wound — —— — — x Round Profile Wound — — — x x x Rectangular Profile Multilayer xx x x — x Annular Tubes

The shapes and sizes of oriented polymeric tubes produced according tothe disclosed methods can vary. As noted herein above, such tubes may becylindrical, but are not limited thereto. Wall thicknesses of theoriented polymeric tubes can vary as well and can be tailored based on,e.g., the polymer film (or profile) thickness (for the planarorientation and annular positioning method), tube/tube precursorthickness (for the multi-layer annular orientation and annularpositioning method), the amount of elongation force applied thereto, andthe number of layers combined to produce the final oriented polymerictube (e.g., the number of wrappings or the number of tube precursors ortubes combined to produce a multi-layer tube). Oriented polymeric tubesprovided according to the present disclosure can be substantiallyhomogeneous in composition (e.g., consisting primarily of a singleoriented crystallizable polymer component), wherein multiple layersthereof may be bonded together with a comparatively small amount of tielayer material (forming an adhesive/tie layer between adjacent layers ofthe oriented polymer. Certain oriented polymeric tubes providedaccording to the present disclosure can be non-homogenous, asfilms/profiles/tubes can be combined which are compositionally different(e.g., tubes may comprise different crystallizable polymers and/ordifferent tie layer materials (which may be stretched or may be inunstretched form), may include/exclude fillers or other components,etc.). The methods outlined herein are broadly applicable to thepreparation of a wide range of oriented polymeric tubes.

In some embodiments, oriented polymeric tubes prepared according to thedisclosed methods can be characterized by the degree of molecularorientation of the crystallizable polymer across a cross-section of thetube (i.e., from the ID to the OD of the tube). Preferably, themolecular orientation of the crystallizable polymer within the tubewalls is substantially unchanged across the cross-section of theoriented polymeric tube. For example, the molecular orientation isgenerally in the same direction and is in about the same amount near theID as near the OD of oriented polymeric tubes according to the presentdisclosure. Such orientation characteristics can be evaluated, e.g.,using x-ray diffraction.

In particular, the molecular orientation profile in certain embodimentsis substantially consistent through a wall of the oriented polymerictube, or is substantially consistent through predefined portions of awall of the oriented polymeric tube. In some embodiments, tubes have amolecular orientation profile characterized by varying levels oforientation through predefined portions of a wall of the orientedpolymeric tube and/or characterized by varying axes of orientationthrough predefined portions of a wall of the oriented polymeric tube.Some tubes provided herein exhibit other profiles, e.g., an increasingmolecular orientation gradient through a wall from the inner diameter tothe outer diameter of the oriented polymeric tube or a decreasingmolecular orientation gradient through a wall from the inner diameter tothe outer diameter of the oriented polymeric tube. In some embodiments,the molecular orientation profile is substantially consistent along thelength of the oriented polymeric tube or that is substantiallyconsistent along predefined portions of a length of the orientedpolymeric tube. In some embodiments, tubes have a molecular orientationprofile characterized by varying levels of orientation along the lengthof the oriented polymeric tube and/or characterized by varying axes oforientation along the length of the oriented polymeric tube.

The compositional profile of an oriented polymeric tube as providedherein, in certain embodiments, is substantially consistent through awall of the oriented polymeric tube or is substantially consistentthrough predefined portions of a wall of the oriented polymeric tube. Inother embodiments, the composition profile can be characterized byvarying compositions through predefined portions of a wall of theoriented polymeric tube. Similarly, the compositional profile of anoriented polymeric tube as provided herein, in certain embodiments, issubstantially consistent along a length of the oriented polymeric tubeor is substantially consistent along a length of the oriented polymerictube. In other embodiments, the composition profile can be characterizedby varying compositions along a length of the oriented polymeric tube.

In certain embodiments, the degradation rate profile can be affected bythe specific methods used for formation of an oriented polymeric tube.For example, oriented polymeric tubes are provided herein which arecharacterized by a degradation rate profile that is substantiallyconsistent through a wall of the oriented polymeric tube, characterizedby a degradation rate profile that is substantially consistent throughpredefined portions of a wall of the polymeric tube, or characterized bya degradation rate profile characterized by varying degradation ratesthrough predefined portions of a wall of the oriented polymeric tube,including a degradation rate profile characterized by an increasingdegradation rate gradient through a wall from the inner diameter to theouter diameter of the polymeric tube and a degradation rate profilecharacterized by a decreasing degradation rate gradient through a wallfrom the inner diameter to the outer diameter of the oriented polymerictube. In some embodiments, oriented polymeric tubes are provided hereinwhich are characterized by a degradation rate profile that issubstantially consistent through a length of the oriented polymerictube, characterized by a degradation rate profile that is substantiallyconsistent along a length of the oriented polymeric tube, orcharacterized by a degradation rate profile characterized by varyingdegradation rates along the length of the oriented polymeric tube,including a degradation rate profile characterized by a degradation rategradient along the length of the oriented polymeric tube.

Advantageously, oriented polymeric tubes provided according to thepresent disclosure can exhibit sufficient strength, e.g., for in vivouse. Such tubes can be characterized as having sufficient compressionstrength/resistance to radial compression to function in the desiredcontext. For example, in some embodiments, oriented polymeric tubesprovided according to the disclosed methods may find use, e.g., asstents or as components of stents. Stents are subjected to heavy loads,e.g., when inserted and left in blood vessels and should exert a radialforce sufficient to ensure that the stent remains in the narrowed spotand prevent constricting of blood vessels. Oriented polymeric tubesprepared by the foregoing methods were tested (e.g., to evaluate cycliccompression), and relevant findings from this testing are describedherein below. Certain oriented polymeric tubes prepared according to theplanar orientation/annular positioning method exhibited higher energyabsorption (normalized for wall thickness) than the comparative material(prepared via traditional extrusion/expansion methods as describedherein). All tested oriented polymeric tubes prepared according to theplanar orientation/annular positioning methods showed improvedhysteretic behavior as measured by the x-intercept at the start of eachcycling period.

It was also found that various parameters of the disclosed methods (andproperties of the disclosed materials) can lead to differences inphysical properties of the resulting oriented polymer tubes, allowingfor flexibility in processing. For example, the physical properties oforiented polymeric tubes can be modified based on the presentdisclosure, e.g., by selecting a polymer with a different molecularweight and/or composition (e.g., including copolymers), by modifying themanner of orientation of the film in the planar orientation/annularpositioning method (e.g., uniaxial vs biaxial), wrapping polymericfilms/profiles at a different angle around a forming mandrel (e.g.,along an axis or on a bias angle), employing different polymerfilms/profiles wrapped together at the mandrel, wrapping such polymerfilms/profiles in different ways (e.g., staggered versus stacked), etc.In some embodiments, the disclosed method comprises arranging aplurality of units of stretched polymeric material (e.g., stretchedfilms/profiles, etc.) in at least one of a stacked manner and astaggered manner, and wrapping the arranged plurality of units ofstretched polymeric material on a bias angle, where the bias angle canvary (including 0°).

The end use of the tubes provided according to the present disclosurecan vary. As referenced herein, the molecular orientation afforded bythe disclosed methods advantageously can provide tubes of relativelyhigh strength (e.g., radial/compression strength), making these tubesparticularly useful where such high strengths are important. One suchapplication is in the context of medical implants such as stents. Thesizes of stents provided according to certain embodiments of thedisclosed method can vary, and may be suitably designed for one or morespecific applications. For example, in some embodiments, the length, Lof the stent may be from about 20 mm to about 200 mm. For example, forsome applications, the stent may have a length, L, of from about 40 mmto 100 mm or any value between, for example, at least about 50 mm, 60mm, 70 mm, 80 mm, or 90 mm. In some applications, the stent may have alength, L, of from about 25 mm to 150 mm or any value between, forexample at least about 50 mm, 75 mm, 100 mm or 125 mm. The stent mayalso be longer or shorter than these exemplary values in other stentapplications. Likewise, in some embodiments, the strut thickness of thestent may be from about 0.7 mm to about 0.4 mm. For example, for someapplications, the stent may have a strut thickness of from about 0.08 mmto 0.15 mm or any value between, for example, at least about 0.09 mm,0.1 mm, 0.12 mm, 0.13 mm, or 0.14 mm. In some applications, the stentmay have a strut thickness of from about 0.15 mm to 0.4 mm or any valuebetween, for example at least about 0.2 mm, 0.25 mm, 0.3 mm or 0.35 mm.The stent may also have a strut thickness greater than or less thanthese exemplary values in other stent applications. Likewise the stentmay be formed with a variety of diameters. In some embodiments themidbody diameter of the stent (the diameter of the stent at a pointequidistant from each end) may be from about 1.5 mm to about 40 mm, suchas a midbody inside diameter of about 2.5 mm to 16 mm or any distancewithin this range such as between about 3 mm to 14 mm or between about 5mm to about 10 mm.

Stents are generally cylindrically shaped devices often used in thetreatment of arterial disease. Arterial disease involves the depositionof lipids within an artery and subsequent plaque formation along thearterial wall. These plaque lesions may be soft or become hard andcalcified and over time reduce the luminal space within the vessel, aprocess known as stenosis. To treat stenosis, stents are commonlydeployed at the treatment site serving to maintain patency of the lumenof the diseased segment of the vessel. Stents must have adequate radialstrength to provide the vessel with adequate radial support to maintainvessel patency.

Stents are commonly manufactured by laser cutting a tube to into aradially expandable geometry comprising interconnected structuralelements or struts. During conventional deployment as with anangioplasty balloon catheter, the stent struts undergo high localizeddeformation, requiring the material from which the stents aremanufactured to be highly deformable while maintaining high strength andrigidity (e.g. the material must exhibit high toughness). In manyclinical treatment applications, the stent is required only temporarily,for example, to maintain patency during a critical healing phase or todeliver an active agent or a drug to a target site.

As such, tubes described herein may find particular use as stents, asthey can, in various embodiments, exhibit high compressive/radialstrength as well as biodegradability/bioabsorbability. The ability totailor the composition and physical properties of the layers thatcomprise each tube, as disclosed herein, allows for the production oftubes exhibiting sufficient compressive/radial strength, as well asbiodegradability, which can, e.g., be completely absorbed after theirclinical utility has ended. The tubes disclosed herein can beprocessed/modified accordingly to serve a desired purpose in thisregard, e.g., by cutting into an appropriate size/geometry.

In other embodiments, the tubes provided according to the presentdisclosure can be used in other contexts, e.g., including but notlimited to, serving as heat shrink tubes to be placed around othertubes/tubular constructs, e.g., to aid in fusing components of suchtubular constructs. In some embodiments, such heat shrink tubes preparedaccording to the disclosed methods exhibit enhanced thermodynamicproperties, including, but not limited to, improved heat shrinkcapabilities.

Although the present disclosure focuses on embodiments comprising atleast one crystallizable (e.g., crystallizable, biodegradable) polymer,it is noted that the principles described herein are not limitedthereto. Although the techniques outlined herein are advantageouslyapplied in the context of such crystallizable polymers to orientmolecules therein for enhanced strength of the resulting tubular form,these principles can provide other benefits as well, which are notlimited to crystallizable polymers (and may be applicable, e.g., toamorphous polymers, including, but not limited to, biodegradableamorphous polymers). As such, in some embodiments, the disclosureprovides methods for subjecting a polymeric material comprising anamorphous biodegradable polymer to planar stretching and annularorientation or to multilayer annular expansion and annular positioningas generally disclosed herein. Typically, such amorphouspolymer-containing products do not exhibit the high strength valuesreferenced herein above with respect to crystallizablepolymer-containing products (which are enhanced, e.g., by molecularorientation), and thus may find use, e.g., in the processing of othertubes (e.g., including, but not limited to, serving as a heat shrinkmaterial to fuse other multi-layer tubes as referenced above) and as acomponent of various devices, e.g., being reinforced by one or moreadditional components.

Many modifications and other embodiments of the invention will come tomind to one skilled in the art to which this invention pertains havingthe benefit of the teachings presented in the foregoing description.Therefore, it is to be understood that the invention is not to belimited to the specific embodiments disclosed and that modifications andother embodiments are intended to be included within the scope of theappended claims. Although specific terms are employed herein, they areused in a generic and descriptive sense only and not for purposes oflimitation.

EXAMPLE 1

A plaque consisting of PL32, a polylactide resin purchased from CorbionPurac, was created via compression-molding to a thickness of 125 μmusing a Carver Press. The PL32 plaque was then stretched uniaxially in aBrückner Lab Stretcher to give a final thickness of around 25 μm. Aplaque consisting of PLC 7015, a copolymer resin of lactide andcaprolactone obtained from Corbion Purac, was created viacompression-molding to yield a thickness of around 40 μm using a CarverPress. The PLC7015 plaque was then stretched biaxially in a Brückner LabStretcher to a final thickness of around 15 μm.

Rectangles were cut out of each of the two films and placed one on topof the other and wrapped around a metal mandrel with OD=2.8 mm with thePL32 film in contact with the mandrel. The films were wrapped such thatthe stretch direction of the PL32 film was aligned in thecircumferential direction. The wrapped mandrel was then covered tightlywith a linear low density polyethylene (LLDPE) film, Cortuff® ShrinkFilm obtained from the Sealed Air Corporation, and taped into place. Theassembly was subsequently placed into a hot air circulating oven set at80° C. for 30 minutes. After the assembly was taken out of the oven, theshrink film was removed, and the now-fused composite tube was slid offof the mandrel. The final mean wall thickness of the composite tube wasaround 130 μm.

EXAMPLE 2

The procedure of Example 1 was repeated starting with a 125 μm plaquemade from PL65 polylactide purchased from Corbion Purac stretcheduniaxially to a final thickness of around 30 μm and a 40 μm plaque madefrom PLC 7015 stretched biaxially to a final thickness of around 15 μm.The pressure-formed tube had a wall thickness of around 140 μm.

EXAMPLE 3

The procedure of Example 1 was repeated using an oven temperature of120° C.

EXAMPLE 4

The procedure of Example 2 was repeated using an oven temperature of120° C.

EXAMPLE 5

The procedure of Example 1 was repeated using an oven temperature of160° C.

EXAMPLE 6

The procedure of Example 2 was repeated using an oven temperature of160° C.

EXAMPLE 7

The procedure of Example 1 was repeated using an oven temperature of180° C.

EXAMPLE 8

The procedure of Example 2 was repeated using an oven temperature of180° C.

Cyclic Compression Testing

The composite tubes from Examples 1 through 8 were tested in compressionon an Instron machine with a 10 lb load cell. The tube was positionedsuch that its length axis was normal to the movement of the jaw. Duringthe test, a disk clamped to the jaw was lowered onto the tube surface.Compression of the tube occurred until the tube had been deformed to 50%of its initial diameter at 50% of its initial diameter per minute,whereupon the jaw moved back up to its starting position at the samerate. The force required to compress the sample was measured by the loadcell and converted to a stress. The procedure was repeated five timesper tube with no dwell between cycles. The values reported were themaximum stress, the energy absorbed by the tube over the five cyclesnormalized for wall thickness, and the recovery of the tube as a percentof the compression extent. This last quantity is an indication of thehysteresis between compression cycles for the tube.

FIGS. 6A, 6B, 6C. show Max Stress, Normalized Energy and X-Interceptfrom cyclic compression tests for the tubes from Example 3 and Example 4compared to a control tube. The control tube was manufactured byextruding and expanding an input tube consisting of PL38 PLLA fromCorbion Purac to a final dimension of 2.8 mm ID with a wall thickness of100 μm. The tube was then annealed at 120° C. for 30 minutes to matchthe pressure-forming time of the composite tubes from Examples 3 and 4.From FIGS. 6A, 6B, 6C, the tube from Ex. 4 shows clear superiority tothe control tube in Max Stress, Normalized Energy and hysteresis betweencycles for all compression cycles. The tube from Ex. 3 shows lower Max.Stress values, but improvements in Normalized Energy and hysteresisbetween cycles.

FIGS. 7A, 7B, 7C. show Max Stress, Normalized Energy and X-Interceptfrom the cyclic compression tests for the Tubes from Examples 1, 3, 5and 7. The effects of forming temperature on these properties arereadily apparent. For the PL32/PLC7015 composite structure disclosed inthe examples, the optimum forming temperature to maximize Max Stress andEnergy is 160° C.

FIGS. 8A, 8B, 8C. show Max Stress, Normalized Energy and X-Interceptfrom the cyclic compression tests for the Tubes from Examples 2, 4, 6and 8. For the PL65/PLC7015 composite structure disclosed in theexamples, the optimum forming temperature to maximize Max Stress andEnergy is 120° C.

EXAMPLE 9

The procedure of Example 3 was repeated starting with a 125 μm plaquemade from PL32 that was stretched biaxially to a final thickness ofabout 10 μm and a 40 μm plaque made from PLC 7015 that was stretchedbiaxially to a final thickness of around 15 μm. The finished compositetube had a mean wall thickness of around 120 μm.

EXAMPLE 10

The procedure of Example 3 was repeated starting with a 125 μm plaquemade from PL32 that was stretched biaxially to a final thickness ofabout 10 μm and a 125 μm plaque made from PLC8516,polylactide-co-caprolactone copolymer purchased from Corbion Purac, thatwas stretched biaxially to a final thickness of about 7 μm. The finishedcomposite tube had a mean wall thickness of around 50 μm.

EXAMPLE 11

The procedure of Example 4 was repeated using a 125 μm plaque made fromPLC8516 that was stretched uniaxially to a final thickness of about 25μm and a 125 μm plaque made from PLC8516, a polylactide-co-caprolactonecopolymer purchased from Corbion Purac, which was stretched biaxially toa final thickness of about 7 μm. The finished composite tube had a meanwall thickness of around 95 μm.

EXAMPLE 12

The procedure of Example 3 was repeated using a 125 μm plaque made fromPLC8516 that was stretched biaxially to a final thickness of about 7 μmand a 45 μm plaque made from PC12, polycaprolactone purchased fromCorbion Purac, that was stretched biaxially to a final thickness ofabout 25 μm. The finished composite tube had a mean wall thickness ofaround 100 μm.

EXAMPLE 13

A 125 μm plaque made from PLC8516 was stretched biaxially to a finalthickness of about 7 μm. A rectangle was cut out of the film and wrappedaround a metal mandrel with OD=2.8 mm. The wrapped mandrel was thencovered tightly with a LLDPE shrink film and taped into place. Theassembly was subsequently placed into a hot air circulating oven set at120° C. for 30 minutes. After the assembly was taken out of the oven,the shrink film was removed, and the now-fused composite tube was slidoff of the mandrel. The final mean wall thickness of the composite tubewas around 90 μm.

EXAMPLE 14

A plaque consisting of PL32 was molded to a thickness of 125 μm andstretched biaxially in a Brückner Lab Stretcher to give a finalthickness of around 15 μm. A plaque consisting of PLC 7015 was molded togive a thickness of 40 μm, and then it was stretched biaxially to yielda final thickness of around 15 μm. A 125 μm plaque made from PLC8516 wasstretched biaxially to a final thickness of about 7 μm. Rectangles werecut out of each of the films, stacked in the order PL32/PLC7015/PLC8516and wrapped around a metal mandrel with OD=2.8 mm. The PL32 film was incontact with the mandrel. The wrapped mandrel was then covered tightlywith a LLDPE film and taped into place. The assembly was subsequentlyplaced into a hot air circulating oven set at 120° C. for 30 minutes.After the assembly was taken out of the oven, the shrink film wasremoved, and the now-fused composite tube was slid off of the mandrel.The final mean wall thickness of the composite tube was around 80 μm.

EXAMPLE 15

A 30 μm wall, 2.8 mm ID extruded and expanded tube made from PL32 resin(PLA) was slid over a mandrel, and the biaxially stretched PL32 film andPLC7015 film from Example 9 were wrapped around the PLA tube with thePLC7015 film contacting the outer circumference of the PLA tube. Thewrapped mandrel was then covered tightly with a LLDPE film and tapedinto place. The assembly was subsequently placed into a hot aircirculating oven set at 120° C. for 30 minutes. After the assembly wastaken out of the oven, the shrink film was removed, and the now-fusedcomposite tube was slid off of the mandrel. The final mean wallthickness of the composite tube was around 130 μm.

What is claimed is:
 1. A method for producing a tube, comprising:obtaining at least one stretched polymeric material exhibiting at leastpartial molecular orientation, wherein: the obtaining the at least onestretched polymeric material comprising stretching at least onepolymeric material, the at least one polymeric material comprising afirst dimension, and at least one crystallizable biodegradable polymericmaterial, and the at least one polymeric material being stretched in amanner that increases the first dimension; and forming the tube usingthe at least one stretched polymeric material.
 2. The method of claim 1,wherein the stretching comprises planar stretching.
 3. The method ofclaim 1, wherein one or more of the at least one polymeric material isone or more of a polymer film, a polymer monofilament, a polymer tape,and a polymer rod.
 4. The method of claim 1, wherein: the at least onepolymeric material has a second dimension, and the stretching the atleast one polymeric material comprises stretching the at least onepolymeric material to increase the second dimension, the at least onestretched polymeric material comprises a biaxially stretched polymericmaterial.
 5. The method of claim 1, wherein the forming comprises usingthe at least one stretched polymeric material and at least one adhesivepolymeric material.
 6. The method of claim 1, further comprising:obtaining the at least one polymeric material based at least in part oncombining the at least one adhesive polymeric material with the at leastone crystallizable biodegradable polymeric material.
 7. The method ofclaim 6, wherein the at least one polymeric material is a compositepolymeric material comprising the at least one crystallizablebiodegradable polymeric material and the at least one adhesive polymericmaterial in layered form.
 8. The method of claim 6, wherein the at leastone adhesive polymeric material and the at least one crystallizablebiodegradable polymeric material are combined before, during, or afterthe at least one polymeric material is stretched.
 9. The method of claim1, wherein the forming the tube comprises wrapping the at least onestretched polymeric material and the at least one adhesive polymericmaterial around a support.
 10. The method of claim 9, wherein thesupport has one or more of a cylindrical shape, a round shape, arectangular shape, a triangular shape, an elliptical shape, a polygonalshape, and a tubular form.
 11. The method of claim 9, wherein thewrapping comprises wrapping the at least one stretched polymericmaterial and the at least one adhesive polymeric material around thesupport multiple times such that the tube comprises multiple layers ofthe at least one stretched polymeric material and multiple layers of theat least one adhesive polymeric material.
 12. The method of claim 9,wherein: the at least one stretched polymeric material comprises aplurality of units of stretched polymeric material, the plurality ofunits of stretched polymeric material comprises different polymericmaterials or a same polymeric material; and the forming the tubecomprises arranging the plurality of units of stretched polymericmaterial in at least one of a stacked manner and a staggered manner, andwrapping the arranged plurality of units of stretched polymeric materialon a bias angle.
 13. The method of claim 9, wherein the support is amandrel, and the method further comprises removing the tube from themandrel.
 14. The method of claim 9, wherein the support comprises adevice.
 15. The method of claim 14, further comprising forming aresulting composite based at least in part on the tube and the support,and the resulting composite is a medical device.
 16. The method of claim1, further comprising forming a medical device based at least in part onthe tube.
 17. The method of claim 16, wherein the forming the medicaldevice comprises: cutting the tube into a stent.
 18. The method of claim17, further comprising applying one or more of a therapeutic, acovering, and a coating to the stent.
 19. The method of claim 1, whereinthe forming the tube comprises subjecting the at least one stretchedpolymeric material to at least one of heat and pressure.
 20. The methodof claim 1, wherein the forming the tube comprises: forming a layeredstructure, the forming the layered structure comprising: applying ashrink tube or shrink film around at least part of the at least onestretched polymeric material to give a layered structure, and subjectingthe layered structure to at least one of heat and pressure.
 21. Themethod of claim 1, wherein the forming the tube comprises: inserting atleast part of the at least one stretched polymeric material in a mold;positioning the at least one stretched polymeric material over anexpandable support; and subjecting the at least one stretched polymericmaterial to at least one of heat and pressure.
 22. The method of claim1, wherein one or more of the at least one crystallizable biodegradablepolymeric material is selected from the group consisting ofpoly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(E-caprolactone)(PCL), polyglycolic acid (PGA), poly(para-dioxanone) (PDO),poly(hydroxybutyrate), poly(hydroxyvalerate), poly(tetramethylcarbonate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG),poly(propylene glycol) (PPG), and copolymers and derivatives andcombinations thereof.
 23. The method of claim 1, wherein the forming thetube comprises using the at least one stretched polymeric material andat least one adhesive polymeric material, and wherein the adhesivepolymeric material is selected from the group consisting ofpoly(ε-caprolactone), poly(trimethylene carbonate), poly(D,L-lactide),poly(L-lactide)-co-ε-caprolactone), poly(L-lactide-co-trimethylenecarbonate), poly(ε-caprolactone-co-trimethylene carbonate),poly(ethylene glycol), poly(L-lactide-co-poly(ethylene glycol)), andcopolymers and derivatives and combinations thereof.
 24. The method ofclaim 5, wherein the forming the tube comprises using the at least onestretched polymeric material and at least one adhesive polymericmaterial, and the at least one crystallizable biodegradable polymericmaterial and the at least one adhesive polymeric material comprise asame polymeric material.
 25. The method of claim 1, wherein the at leastone stretched polymeric material is stretched at least ten percent of amaximum stretch ratio respectively corresponding to the at least onepolymeric material.
 26. The method of claim 1, wherein the stretchingthe at least one polymeric material comprises controlling, during thestretching, one or more of a mechanical property, a thermodynamicproperty, a chemical property, an electrical property, and a degradationrate, of the at least one polymeric material.
 27. The method of claim 1,wherein the at least one polymeric material is stretched between threehundred percent and one thousand percent of an original dimension of theat least one polymeric material.
 28. A method, comprising: obtaining atleast one stretched polymeric material exhibiting at least partialmolecular orientation, wherein: the at least one stretched polymericmaterial corresponds to at least one polymeric material comprising afirst dimension, and at least one crystallizable biodegradable polymericmaterial, and the at least one polymeric material having been stretchedin a manner that increased the first dimension; and forming a tube usingthe at least one stretched polymeric material.
 29. A tube, comprising:at least one stretched polymeric material exhibiting at least partialmolecular orientation, the at least one stretched polymeric materialbeing obtained based at least in part on stretching at least onepolymeric material, wherein the at least one polymeric materialcomprises a first dimension, and at least one crystallizablebiodegradable polymeric material, the at least one polymeric material,and wherein the at least one polymeric material is stretched in a mannerthat increases the first direction.
 30. A tube, wherein: the tubecomprises at least one crystallizable biodegradable polymeric material,and an outer surface that has a normal that is perpendicular to a lengthof the tube, and the tube exhibits: a maximum stress value of about 20MPa or greater measured based on a first compression cycle; and the tubebeing deformed 17% or less in at least a first dimension after the firstcompression cycle.
 31. The tube of claim 30, wherein the firstcompression cycle comprises: obtaining an initial distance between twoparallel plates between which the tube is disposed, the two parallelplates contacting the outer surface of the tube in a manner in which thetwo parallel plates provide substantially no load on the tube;compressing the plates to a distance that is 50% of the initial distanceat a rate of 50% of the initial distance of the two parallel plates perminute, the compressing the plates causing the tube to deform in thefirst direction, the first direction being a direction in which theplates are compressed; and releasing a compression of the plates on thetube at a rate of 50% of the initial distance of the two parallel platesper minute.
 32. The tube of claim 30, wherein a total energy value underan engineering stress-strain curve corresponding to the tube after thefirst compression is at least 138 kgf·mm/cm.
 33. The tube of claim 30,wherein the tube has one or more of a therapeutic, a covering, and acoating applied thereon.
 34. A tube, wherein: the tube comprises atleast one crystallizable biodegradable polymeric material, and an outersurface that has a normal that is perpendicular to a length of the tube,the tube exhibits a maximum stress value of about 20 MPa or greatermeasured based on a first compression cycle; and a total energy valueunder an engineering stress-strain curve corresponding to the tube afterthe first compression is at least 138 kgf·mm/cm.